Obesity, the most prevalent of body weight disorders, is the most important nutritional disorder in the western world, with estimates of its prevalence ranging from 30% to 50% within the middle-aged population. Obesity, defined as an excess of body fat relative to lean body mass, also contributes to other diseases. For example, this disorder is responsible for increased incidence of diseases such as coronary artery disease, hypertension, stroke, diabetes, hyperlipidemia, and some cancers (See, e.g., Nishina, P. M. et al., 1994, Metab. 43: 554-558; Grundy, S. M. & Barnett, J. P., 1990, Dis. Mon. 36: 641-731). Obesity is not merely a behavioral problem, i.e., the result of voluntary hyperphagia. Rather, the differential body composition observed between obese and normal subjects results from differences in both metabolism and neurologic/metabolic interactions. These differences seem to be, to some extent, due to differences in gene expression, and/or level of gene products or activity. The nature, however, of the genetic factors which control body composition are unknown, and attempts to identify molecules involved in such control have generally been empiric, and the parameters of body composition and/or substrate flux have not yet been identified (Friedman, J. M. et al., 1991, Mammalian Gene 1:130-144).
The epidemiology of obesity strongly shows that the disorder exhibits inherited characteristics (Stunkard, 1990, N. Eng. J. Med. 322:1483). Moll et al., have reported that, in many populations, obesity seems to be controlled by a few genetic loci (Moll et al. 1991, Am. J. Hum. Gen. 49:1243). In addition, human twin studies strongly suggest a substantial genetic basis in the control of body weight, with estimates of heritability of 80-90% (Simopoulos, A. P. & Childs B., eds., 1989, in “Genetic Variation and Nutrition in Obesity”, World Review of Nutrition and Diabetes 63, S. Karger, Basel, Switzerland; Botjeson, M., 1976, Acta. Paediatr. Scand. 65:279-287).
In other studies, non-obese persons who deliberately attempted to gain weight by systematically over-eating were found to be more resistant to such weight gain and able to maintain an elevated weight only by very high caloric intake. In contrast, spontaneously obese individuals are able to maintain their status with normal or only moderately elevated caloric intake. Studies of the genetics of human obesity, and of animal models of obesity demonstrate that obesity results from complex defective regulation of both food intake, food induced energy expenditure, and of the balance between lipid and lean body anabolism. It has now been established that the maintenance of body weight, satiety and energy expenditure is a complex process, regulated at various levels, including external and hypothalmic control of satiety, neuroendocrine and sympathetic nervous system control of metabolic processes, as well as enzymatic and transcriptional controls of utilization of glucose, and adipogenesis (Kahn, 2000, Nature Genetics 25: 6; and Palou, et al., 2000, Eur. J. Nutr. 39: 127).
It is estimated that approximately 40% of calories in the western diet are from fat. Thus, blocking absorption of a fraction of such fat would lead to weight loss. The pathways involved in fatty acid absorption in the small intestine are fairly well understood. Fatty acids are liberated from triglycerides in the lumen of the small intestine through the action of pancreatic lipase. Free fatty acids then cross the plasma membrane of the enterocytes, a transport mechanism probably utilizing FATP4, and, once in the enterocyte, are re-esterified into triacylglycerols, the major form of energy stored in adipose tissue, which are packaged into chylomicrons prior to absorption.
Although production of diacylglycerol can be accomplished through various mechanisms, the final rate-limiting step in biosynthesis of triaclyglycerol is accomplished via the enzyme diacyl glycerol acyltransferase (DGAT). Although it has been known that DGAT activity is increased in obese rodents, DGAT1 deficient mice are resistant to high fat-diet induced obesity and have increased energy expenditure (Smith, 2000, Nature Genetics 25: 87). Until recently when a second DGAT enzyme (DGAT2) was identified, it was believed a single enzyme was responsible for synthesis of triacylglycerol (Cases et al. 2001 J. Biol. Chem. 276: 38870). An understanding of regulation and maintenance of this rate limiting step of triglyceride can provide insight into the regulation of production and maintenance of energy stores and fat, and assist in the development of treatment for obesity and related disorders involving production of triacylglycerols.
Given the importance of understanding body weight homeostasis and, further, given the severity and prevalence of disorders, including obesity, which affect body weight and body composition, there exists a great need for the systematic identification of genes and regulation of genes involved in these complex processes and disorders. Such identification will provide rationales and facilitate development of specific compounds acting via modulation of metabolic activity for use in the treatment of obesity and related disorders.